Research on cannabinoids has progressed tremendously since the discovery of specific recognition sites (receptors) for chemicals like 9-tetrahydrocannabinol (THC), the main active ingredient in marijuana. The endocannabinoid signaling system (ECS) thus likely serves as the biological substrate for the marijuana high. This subjective state presumably underlies human marijuana consumption that may lead to compulsive cannabis intake and dependence disorders. Drug discrimination is a powerful, pharmacologically selective model for assessing subjectively experienced drug effects in animals (and man) and is the major in vivo behavioral technique in this application. Cannabinoid receptor CB1 (CB1R) agonists and antagonists will be trained in drug discrimination using different doses, providing for in vivo assays with different sensitivity levels. This is complemented by observational studies and schedule controlled responding allowing for an in depth characterization of ligands. A major aim of this research is to identify new medications that will translate into better pharmacotherapies for combating marijuana addiction. Alleviation of withdrawal-related effects in physically dependent individuals likely is an important motivational factor in addiction processes. New molecules are designed and synthesized by on site expertise. One focus is to identify and refine in vivo neutral CB1R antagonists. Most current CB1R antagonists also display intrinsic activity (inverse agonism) that may hamper patient compliance in treatment settings. Thus, the studies will expand our understanding of the ECS, comprised of two major endogenous signaling molecules, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) acting on two known receptors, CB1 and CB2, in normal body function and pathophysiology. Additional therapeutic targets for the application concern ligands selectively affecting the enzymes involved in the deactivation of the endocannabinoids, thus potentially avoiding direct receptor activation. The behavioral studies are aided by neuro/biochemical procedures provided by collaborating faculty in pursuing these goals. In addition to AEA, recent developments regarding 2-AG allow for a much more comprehensive understanding of this major endocannabinoid in ECS signaling. By obtaining information on the functions of the endogenous substances (AEA and 2-AG) and the exogenous THC, as well as in vivo neutral blocking agents, these studies will not only further our understanding of ECS signaling in the behavioral neurobiology of cannabis abuse / dependence, but may also lead to the development of effective medications for treating disorders involving cannabis / marijuana, and designer THC-like cannabimimetics. PUBLIC HEALTH RELEVANCE: A major societal concern in the United States is addiction disorders, including cannabis dependence. Although progress has been made, there are no officially accepted pharmaceutical treatments to alleviate marijuana withdrawal symptoms and to reduce the likelihood of relapse once initial sobriety has been achieved. The goals of the current research application are aimed at assisting in filling those gaps.